Attractive electrostatic protein–protein interactions
(PPI)
necessarily involve identifying oppositely charged regions of the protein surface that interact
favorably. This cannot be done reliably if one only considers a single
protein in isolation unless there are obvious charge “patches”
that result in extreme molecular dipoles. Prior work [J. Pharm. Sci.2019108120132] identified three monoclonal antibodies (MAbs) that displayed
experimental behavior ranging from net repulsive to strongly attractive
electrostatic interactions. The present work provides a systematic
computational approach for identifying the origin of diverse PPI,
in terms of which sets of amino acids or individual amino acids are
most influential, and determining if there are different patterns
of pairwise amino acid interaction “maps” that result
in different behaviors. The charge was eliminated computationally,
one by one, for each charged residue in the wild-type sequences, which
resulted in predicted changes in the second osmotic virial coefficient.
The results highlight interaction “maps” that correspond
to cases with qualitatively different net electrostatic PPI for the
different MAbs and solution conditions, as well as key sets of residues
that contribute to strongly attractive PPI. A more computationally
efficient method is also proposed to identify key amino acids based
on Mayer-weighted interaction energies.
This
final communication, of a nine part publication series, details
the process development history for the final synthetic step to prepare
the drug substance BMS-663068 tris(hydroxymethyl)aminomethane
(TRIS) salt. The challenge of developing a robust commercial process
to prepare BMS-663068-TRIS salt (active pharmaceutical ingredient,
API) was achieved by studying the underlying mechanisms that governed
key processing characteristics. Eliminating a slurry-to-slurry transformation
results in predictable reaction kinetics and control of impurity formation.
Key powder property aspects, such as specific surface area and bulk
density, were controlled by examining the impact of seed age, crystallization
relative supersaturation (RSS), and particle attrition due to agitation
during drying. Ultimately, the processing parameters established for
preparation of this drug substance resulted in the generation of the
target compound with consistent quality, powder properties, and yield
across multiple batches.
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